Colorectal adenomas and the C677T MTHFR polymorphism: Evidence for gene-environment interaction?

5,10-Methylene-tetrahydrofolate reductase (MTHFR), an enzyme in folate meta bolism, may play a role in the etiology of colorectal adenomas via effects on DNA methylation and nucleotide synthesis. We investigated the associatio n between a common polymorphism (C677T, reduced MTHFR activity) and colorec tal adenomas within the Minnesota CPRU case-control study. Cases (n = 527) were diagnosed with colonoscopically confirmed adenomas; controls (n = 645) were derived from the same gastroenterology practice and were polyp free a t colonoscopy. Dietary intakes were obtained from a self-administered food- frequency questionnaire prior to colonoscopy. Age- and sex-adjusted odds ra tios (ORs) and 95% confidence intervals for the MTHFR genotype were 0.9 (0. 7-1.2; CT versus CC wild-type) and 0.8 (0.6-1.3; TT versus CC). The associa tions between dietary intakes of folate, vitamin B-12, vitamin B-6, or meth ionine and risk of adenomas showed consistent patterns dependent upon MTHFR genotype, Individuals with the TT genotype and intakes of any of these nut rients in the lowest tertile were at elevated risk for adenomas (about 2-3- fold when compared with TT genotype with high intakes). These trends were m ore pronounced among individuals over age 60, resulting in a 3-6-fold incre ase for low intakes of folate, B-12, and B-6. An increased risk with increa sing alcohol consumption was observed only among those with the CC genotype (P-trend = 0.005); among those with the TT genotype, those with moderate a lcohol consumption were at lowest risk (P for interaction P = 0.02). In con clusion, nutrients involved in the MTHFR metabolic pathway may modify the r elationship between the MTHFR C677T polymorphism and colorectal adenomas, L ow intakes of folate, vitamin B-12, and vitamin B-6 increase risk among tho se (particularly the elderly) with the MTHFR TT genotype.